Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors

  1. Christopher A Natale
  2. Elizabeth K Duperret
  3. Junqian Zhang
  4. Rochelle Sadeghi
  5. Ankit Dahal
  6. Kevin Tyler O'Brien
  7. Rosa Cookson
  8. Jeffrey D Winkler
  9. Todd W Ridky  Is a corresponding author
  1. Perelman School of Medicine, University of Pennsylvania, United States
  2. University of Pennsylvania, United States

Abstract

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.

Article and author information

Author details

  1. Christopher A Natale

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    Christopher A Natale, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.
  2. Elizabeth K Duperret

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Junqian Zhang

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Rochelle Sadeghi

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  5. Ankit Dahal

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Kevin Tyler O'Brien

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  7. Rosa Cookson

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  8. Jeffrey D Winkler

    Department of Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    Jeffrey D Winkler, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.
  9. Todd W Ridky

    Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    ridky@mail.med.upenn.edu
    Competing interests
    Todd W Ridky, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#803381) of the University of Pennsylvania.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Version history

  1. Received: February 9, 2016
  2. Accepted: April 11, 2016
  3. Accepted Manuscript published: April 26, 2016 (version 1)
  4. Version of Record published: May 11, 2016 (version 2)

Copyright

© 2016, Natale et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 6,059
    Page views
  • 1,038
    Downloads
  • 81
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Christopher A Natale
  2. Elizabeth K Duperret
  3. Junqian Zhang
  4. Rochelle Sadeghi
  5. Ankit Dahal
  6. Kevin Tyler O'Brien
  7. Rosa Cookson
  8. Jeffrey D Winkler
  9. Todd W Ridky
(2016)
Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors
eLife 5:e15104.
https://doi.org/10.7554/eLife.15104

Further reading

    1. Cell Biology
    2. Structural Biology and Molecular Biophysics
    Bronwyn A Lucas, Benjamin A Himes, Nikolaus Grigorieff
    Research Advance

    Previously we showed that 2D template matching (2DTM) can be used to localize macromolecular complexes in images recorded by cryogenic electron microscopy (cryo-EM) with high precision, even in the presence of noise and cellular background (Lucas et al., 2021; Lucas et al., 2022). Here, we show that once localized, these particles may be averaged together to generate high-resolution 3D reconstructions. However, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias while retaining the benefits of high-precision localization, and we show that molecular features not present in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution. Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.

    1. Cell Biology
    2. Immunology and Inflammation
    Yijun Zhang, Tao Wu ... Li Wu
    Research Article

    Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.